In animal cells, nine aminoacyl-tRNA synthetases are associated with the three auxiliary proteins p18, p38, and p43 to form a stable and conserved large multi-aminoacyl-tRNA synthetase complex (MARS), whose molecular mass has been proposed to be between 1.0 and 1.5 MDa. The complex acts as a molecular hub for coordinating protein synthesis and diverse regulatory signal pathways. Electron microscopy studies defined its low resolution molecular envelope as an overall rather compact, asymmetric triangular shape. Here, we have analyzed the composition and homogeneity of the native mammalian MARS isolated from rabbit liver and characterized its overall internal structure, size, and shape at low resolution by hydrodynamic methods and small-angle x-ray scattering in solution. Our data reveal that the MARS exhibits a much more elongated and multi-armed shape than expected from previous reports. The hydrodynamic and structural features of the MARS are large compared with other supramolecular assemblies involved in translation, including ribosome. The large dimensions and non-compact structural organization of MARS favor a large protein surface accessibility for all its components. This may be essential to allow structural rearrangements between the catalytic and cis-acting tRNA binding domains of the synthetases required for binding the bulky tRNA substrates. This non-compact architecture may also contribute to the spatiotemporal controlled release of some of its components, which participate in non-canonical functions after dissociation from the complex.

Poisoning by organophosphorus nerve agents and pesticides is a serious public and military health issue with over 200 000 fatalities annually worldwide. Conventional emergency treatment consists of rapid administration of atropine and pyridinium oxime as an antidote. The reactivation of acetylcholinesterase (AChE) in the central nervous system (CNS) by the oxime is inefficient due to the fact that positively charged pyridiniums do not readily cross the blood brain barrier (BBB). Herein, we described the synthesis and in vitro evaluation of four donepezil-based non quaternary reactivators. The compounds 1–4 have been prepared in 7–8 linear steps in 1–9% overall yields and oximes 1–3 show better ability (8 fold higher) than pralidoxime to reactivate VX-inhibited human AChE (VX-hAChE). Besides, oxime 2 is 5 to 11 fold more efficient than pralidoxime and HI-6 respectively for the reactivation of VX-inhibited human butyrylcholinesterase (VX-hBChE).